Syntenin1/MDA-9 (SDCBP) induces immune evasion in triple-negative breast cancer by upregulating PD-L1
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Syntenin1/SDCBP (syndecan binding protein), also known as melanoma differentiation associated gene-9 (MDA-9), is a PDZ domain-containing molecule, which was initially identified as a key oncogene in melanoma. However, the role of syntenin1 in triple-negative breast cancer (TNBC), especially in suppression of antitumour immune response, remains unknown.
Methods and Results
One hundred TNBC tissues were obtained after radical resection and used for analysis. High syntenin1 expression was associated with increased tumour size (r = 0.421, P < 0.001), presence of lymph node metastasis (r = 0.221, P = 0.044) and poor overall survival (P = 0.01) and recurrence-free survival (P = 0.007). Syntenin1 overexpression significantly promoted 4T1 tumour growth and lung metastasis in BALB/c mice by affecting CD8+ T cells. Western blot and flow cytometry analyses demonstrated that syntenin1 induced CD8+ T cell apoptosis in vitro and in vivo through upregulating PD-L1. Western blot demonstrated that syntenin1 upregulated PD-L1 expression by inducing Tyr705 stat3 phosphorylation, which was further confirmed by stat3 inhibition study. The correlation between syntenin1 and PD-L1 was further confirmed using tumour tissues derived from patients with TNBC (r = 0.509, P < 0.001). Efficacy studies indicated that 4T1-scramble tumour benefitted from anti-PD-L1 therapy (P < 0.001); however, 4T1-syntenin1-KD demonstrated no response to anti-PD-L1 treatment (P = 0.076).
Syntenin1 exhibits a profound function in mediating T cells apoptosis by upregulating PD-L1 and thus could be used as a prognostic biomarker of TNBC. Tumoural syntenin1 expression corelated with anti-PD-L1 treatment efficacy. Targeting syntenin1-mediated T-cell suppression could be a potential strategy for improving the prognosis of patients with TNBC.
KeywordsTriple negative breast cancer Syntenin1 PD-L1 CD8+ T cell apoptosis Immune suppression
The Science &Technology Development Fund of Tianjin Education Commission for Higher Education. (2017KJ198); The Foundation of Tianjin Medical University (2016KYZQ17).
- 2.Collignon J, Lousberg L, Schroeder H, Jerusalem G (2016) Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer (Dove Med Press) 8:93–107Google Scholar
- 13.Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, Boccia R, Lippman ME, Somer R, Smakal M et al (2017) Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN solid tumor study. Breast Cancer Res Treat 167(3):671–686CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, Freeman GJ, Ferris RL (2016) Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNgamma that induce PD-L1 expression in head and neck cancer. Cancer Res 76(5):1031–1043CrossRefPubMedGoogle Scholar
- 19.Janse van Rensburg HJ, Azad T, Ling M, Hao Y, Snetsinger B, Khanal P, Minassian LM, Graham CH, Rauh MJ, Yang X: The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Res 2018Google Scholar
- 20.Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, Wang HY, Wysocka M, Cheng M, Ruggeri BA et al (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A 105(52):20852–20857CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Qian XL, Zhang J, Li PZ, Lang RG, Li WD, Sun H, Liu FF, Guo XJ, Gu F, Fu L (2017) Dasatinib inhibits c-src phosphorylation and prevents the proliferation of triple-negative breast cancer (TNBC) cells which overexpress syndecan-binding protein (SDCBP). PLoS One 12(1):e0171169CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Stier S, Totzke G, Grunewald E, Neuhaus T, Fronhoffs S, Sachinidis A, Vetter H, Schulze-Osthoff K, Ko Y (2000) Identification of syntenin and other TNF-inducible genes in human umbilical arterial endothelial cells by suppression subtractive hybridization. FEBS Lett 467(2–3):299–304CrossRefPubMedGoogle Scholar